Lupus Advances

Etiology

Treatment and Health Maintenance

Role of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Epidemiologic studies may yield further clues about the cause of lupus. For example, SLE is more prevalent in women, especially those in the reproductive years, than in men. And, while people of all races get lupus, the incidence rate for African-American women is three times higher than it is for Caucasian women. African-American women also tend to develop the disease at a younger age, develop more serious complications, and have a higher mortality rate from the disease than do Caucasian women. Researchers are trying to find out why lupus is more common in these populations.

Health professionals continue to search for better ways to care for lupus patients. Answers to what causes the disease and why certain people are more likely to develop it may one day lead to promising new treatments for or even prevention of the disease. In the meantime, researchers continue to look for new treatments and ways to modify existing ones to diminish or eliminate side effects and to improve quality of life for people who have lupus.

During the last decade, there has been a tremendous amount of progress in lupus research. The number of studies on this disease has increased exponentially, and most researchers believe that answers to some of the key questions are close at hand. This chapter highlights some of the recent research advances in lupus and provides an overview of the direction of current research.

Etiology

Investigators have found evidence to support several likely possibilities in the etiology of SLE. Some believe there may be more than one type of SLE and that its etiology may vary from one person to the next. Current studies are focusing on the following elements:

• immune system dysfunction
• genetics
  
• environmental influences
  
• hormones

In lupus research, as in many areas of research, animal models have played an important role. This discussion of the etiology of lupus includes examples of research conducted in animal models that illustrate how these factors might influence the development of SLE in humans.

Immune System Dysfunction
Lupus is an autoimmune disease, so called because a person’s immune system attacks her or his own tissues. In lupus, the signs and symptoms of the disease can be attributed to damage caused directly by antibodies, the deposition of immune complexes (the combination of antigen and antibody), or cell-mediated immune mechanisms. A number of steps are involved in these mechanisms, and scientists hope to reveal the cause of lupus by examining each step. In the process of doing so, they also may find new ways to treat lupus.

One of the hallmarks of lupus is the formation of autoantibodies, which are antibodies that react with a person’s own tissue. Autoantibodies occasionally can be present in healthy people, but they are typically found in low concentrations. Essentially all patients with lupus have autoantibodies, generally in high concentrations. The autoantibodies found in lupus patients are often called antinuclear antibodies because they generally target the nucleic acids, proteins, and ribonucleoprotein complexes inside a cell’s nucleus. Other autoantibodies in lupus patients also can bind to cell surface membranes and destroy cells directly.

Research studies have shown an association between the presence of certain autoantibodies and particular manifestations of lupus, such as kidney or skin disease. Scientists are now trying to establish whether these autoantibodies actually cause signs or symptoms of lupus. However, most people with lupus test positive for many different autoantibodies, so it is often very difficult to identify which autoantibodies are responsible for a specific type of tissue damage in human subjects.

In lupus, the immune system produces too many autoantibodies and forms too many immune complexes. Normally, antigen-antibody immune complexes are joined by complement, a substance in the blood that aids in the breakup and removal of immune complexes from the body. Scientists have found that SLE patients have both inherited and acquired abnormalities in complement and complement receptors. These deficiencies in complement may decrease the body’s ability to get rid of immune complexes. Immune complexes not broken up may be deposited in various body tissues, leading to the inflammation that results in tissue damage. Scientists continue to study

• the nature of immune complexes and what happens to them once they are formed,
  
• the nature of the autoantibodies that make up the immune complexes, and
  
• the reason for increased production of autoantibodies.

Genetics
There is considerable evidence showing that genes play a role in the etiology of lupus. The extremely high occurrence of lupus in identical twins and the increased prevalence of lupus among first- and second-degree relatives of lupus patients suggests a genetic component. In addition, when researchers look at autoantibodies typically found in a lupus patient and her or his siblings and compare them with clinical manifestations of the disease in the individuals, they find that the individuals have the autoantibodies in common more often than they have the clinical manifestations in common. This finding indicates a genetic basis for the formation of autoantibodies that play a role in lupus.

Studies to date suggest that many different genes contribute to lupus susceptibility and that no single genetic abnormality causes the disease. It also appears that genes may be influential in determining the type or severity of lupus. For example, among African Americans with lupus, those with lupus nephritis are more likely than those with other clinical manifestations to have the gene for a form of a receptor that has a low efficiency for capturing immune complexes.

Other genes that have been associated with lupus in humans include

• the immune system genes human leukocyte antigen (HLA)-DR3 (and B8 in older data), HLA-DR2, and complement C4 genes;
• alleles at HLA-DR and HLA-DQ, which are associated with certain autoimmune characteristics found in lupus; and
• a polymorphism of the T-cell receptor, which has been associated with anti-Ro, one of the autoantibodies commonly found in mothers of babies with neonatal lupus erythematosus.

Researchers studying lupus in animals have recently discovered a single gene that causes a lupus-like illness in mice. In these mice, the fas gene, one of the genes that controls apoptosis (programmed cell death), is defective. When the defective fas gene is replaced with a normal gene, the mice no longer develop signs of the disease.

Scientists continue to study the genetics of lupus in humans and in animals. If the genes that create a genetic predisposition for lupus can be identified, it may be feasible to correct genetic defects through gene therapy or other treatments. At this time, researchers are studying

• genes associated with the clearance of immune complexes,
• genetic markers associated with immune abnormalities in lupus, and
• genes associated with apoptosis in lupus.

Environmental Influences
Researchers believe that genetic predisposition is just one piece of the puzzle of lupus etiology. Studies have shown that the occurrence of lupus is high among both members of a pair of identical twins and much lower among nonidentical twins and other full siblings. The fact that this concordance is not 100% among identical twins, however, suggests that environmental agents probably trigger lupus in individuals with a genetic predisposition. Environmental factors that scientists are considering include sunlight, stress, certain chemical substances, and infectious agents such as viruses.

Sunlight
Exposure to the UV rays of sunlight can lead to a skin rash and exacerbate systemic manifestations of lupus. Exposure to UVB light causes certain cellular proteins to accumulate in abnormally large amounts on the cell’s surface. These proteins react with autoantibodies commonly found in people with SLE, leading to a local or systemic inflammatory response.

Stress
Doctors suspect stress is a possible trigger for lupus flares. Frequently, patients ascribe their first symptoms or worsening symptoms to a stressful event, such as divorce, death of a loved one, or job loss. Scientists do not have a clear explanation for this phenomenon, but research is being done to find out whether stress hormones such as adrenaline or cortisone may influence the development or course of the disease.

Chemical Substances
A number of drugs cause a lupus-like illness in susceptible individuals, including chlorpromazine, hydralazine, isoniazid, methyldopa, and procainamide. When the offending drug is stopped, the lupus symptoms resolve. When researchers determine how these drugs cause lupus, they may be able to provide further answers on the etiology of SLE.

Viruses
Many researchers suspect that infectious agents, such as viruses, may trigger lupus, somehow disrupting cellular immune function in susceptible individuals. It is possible that the virus infects B cells (cells programmed to produce antibodies in response to specific antigens) and causes them to produce autoantibodies. Researchers are studying various mechanisms by which viruses could result in autoimmunity.

Hormones
SLE is more prevalent in women during their reproductive years. In addition, disease activity sometimes flares during pregnancy or during the postpartum period. For these reasons, researchers have long considered that hormones may influence lupus. Some research in animals also supports this supposition. Lupus-like illnesses in animals are exacerbated when they receive female hormones. Studies are under way to find out more about how hormones may influence the course and development of lupus.

Improving current treatments for lupus patients and improving the reproductive health of women with lupus are also important elements of ongoing lupus research. Specifically, investigators are studying ways to

• minimize the use of immunosuppressives, such as corticosteroids and cyclophosphamide, to decrease unwanted side effects and improve the quality of life for lupus patients;
  
• develop new therapies with fewer side effects;
  
• correct underlying immune abnormalities; and
  
• improve women’s reproductive health and evaluate the safety of hormone replacement therapy for women with lupus.

Minimize the Use of Immunosuppressives
Corticosteroids, such as prednisone, are a mainstay of lupus therapy because they suppress the immune system and reduce inflammation. Unfortunately, they also cause some serious side effects, including osteonecrosis, osteoporosis, and coronary artery disease. Other, less serious side effects can also take a toll on the patient’s quality of life. Scientists are investigating how corticosteroid use can be minimized in such a way that their benefits are retained while their sides effects are reduced.

Cyclophosphamide also suppresses the immune system and has anti-inflammatory properties. Treatment with cyclophosphamide improves many severe manifestations of lupus. Unfortunately, cyclophosphamide can be toxic. Patients using this drug may experience gastrointestinal complications, alopecia, and an increased risk for infections. In the long term, cyclophosphamide also may damage gonadal tissue and lead to ovarian or testicular failure. Other potential long-term complications include hemorrhagic cystitis, bladder fibrosis, and bladder cancer. At this time, scientists are conducting studies to better understand the long-term effects of cyclophosphamide therapy. In addition, they are exploring the use of additional drugs that might counteract some of the negative side effects of cyclophosphamide, and trying to find the most effective dose regimen that causes the fewest severe side effects.

Scientists are also trying to identify combination therapies that may be more effective than single-treatment approaches. For example, in lupus nephritis patients with moderate kidney scarring, a combination of cyclophosphamide and prednisone is more effective in preserving renal function than is treatment with prednisone alone. In these patients, the combination therapy reduces the likelihood of end-stage renal failure.

Develop New Therapies
While some researchers are examining existing drug and treatment practices, other researchers are developing new treatment regimens. Promising areas of treatment research include biologic agents, hormones, newer forms of chemotherapy, and nitric oxide.

Biologic Agents
On the basis of new information about the SLE disease process, scientists are using novel biologic agents to selectively block parts of the immune system. Developing and testing these new drugs, which are based on compounds that occur naturally in the body, is an exciting and promising new area of lupus research. Scientists hope that these naturally occurring substances will cause few side effects. In addition, use of these agents may yield clues to the etiology of the disease.

Hormones
Because hormones are believed to influence the course and perhaps even the etiology of lupus, many researchers are interested in testing the effects of hormones on lupus patients. For example, animal and human studies have shown benefits associated with dehydroepiandrosterone (DHEA) therapy. DHEA is a naturally occurring hormone present in unusually low concentrations in people with lupus. DHEA is currently being tested in clinical trials to determine if its use can improve the clinical outcome and reduce the prednisone requirements of lupus patients.

Chemotherapy
Researchers also continue to look for new forms of chemotherapy that work selectively on the immune system. For example, they are testing immunosuppressive drugs, such as cyclosporine and 2 chlorodeoxyadenosine, which strongly suppress immune function. Preliminary clinical studies suggest that these drugs may be used in treating patients with lupus nephritis.

Nitric Oxide
Recent studies sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have investigated the role of nitric oxide, a natural substance known to promote inflammation. These studies, using mice that develop a lupus-like autoimmune illness, including joint and kidney inflammation, showed that the animals produce abnormally high levels of nitric oxide. When the mice were treated with a drug that blocks nitric oxide formation, development of kidney disease was prevented and joint inflammation was reduced. Additional studies are needed to determine whether nitric oxide plays a role in inflammatory disease in humans and whether drugs that block the formation or action of nitric oxide will be valuable in treating patients with lupus.

Correct Underlying Immune Abnormalities
Researchers predict that one day it may be possible to correct the underlying immune abnormalities in people with lupus. Studies are under way to explore the dimensions, risks, and benefits of reconstructing the immune system by bone marrow transplantation and of using gene therapy to treat lupus.

Improve Reproductive Health in Women With Lupus
Because of recent improvements in diagnostic tools for lupus and a better understanding of the disease, doctors can now predict the likelihood of a lupus-related miscarriage and identify women at risk for giving birth to babies with neonatal lupus. Doctors and lupus patients can now take measures to prevent miscarriages, and doctors can prepare to treat those babies born with neonatal heart block, the most serious complication of neonatal lupus.

Progress is also being made in another important area of reproductive health. In the past, women with lupus have not been able to use oral contraceptives or take advantage of hormone replacement therapy because of concerns that estrogens exacerbate lupus. However, recent data suggest these drugs may be safe for some women with lupus, and a current study funded by NIAMS, the NIH Office of Research on Women’s Health, and the NIH Office of Research on Minority Health is focusing on the safety and effectiveness of oral contraceptives and hormone replacement therapy in women with lupus. This clinical trial is called the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA). Researchers hope this study will yield options for safe, effective methods of contraception for young women with lupus as well as options for estrogen replacement therapy for postmenopausal women with lupus.

Role of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIAMS leads and coordinates the Federal biomedical research effort in lupus by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies and by disseminating information on research results.

NIAMS funds many scientists across the United States who are studying the causes and mechanisms of tissue injury in SLE and why lupus strikes women and certain minority populations more frequently. In addition, NIAMS has established the first Specialized Centers of Research (SCORs) devoted to lupus. These centers enable basic scientists and clinicians to collaborate closely on lupus research.

To further the study of the genetics of lupus and to provide a resource for all researchers in this field, NIAMS has established a lupus registry and repository. Researchers who study families in which two or more members have been diagnosed with lupus collect and continually update clinical, demographic, and laboratory data on these individuals and submit the data to the lupus registry. Blood, cell, and tissue samples and DNA from these individuals will be stored in the lupus repository.

The registry and repository will allow all lupus researchers access to an enormously valuable database of information on lupus patients. For example, researchers will be able to analyze each DNA sample in the repository for the presence of a standard set of genetic markers. A centralized database will maintain this genetic information along with clinical and laboratory information from the registry. Together, these data can be used as the starting point for genetic analysis to identify possible lupus genes. Finding the genes that cause the disease may help researchers develop new treatments. In addition, this research will help identify which lupus patients will develop the most severe manifestations of the disease. This will help doctors decide who needs the most aggressive treatment.

The research advances of the past have led to significant improvements in the prognosis for patients with lupus. As current research efforts unfold, there is continued hope for new treatments, further improvements in patient quality of life, and ultimately, for ways in which to prevent or cure the disease.

       
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January 26, 1999